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1 ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES 1

2 Bromocriptine containing medicinal products with Marketing Authorisation in the European Union Member State Marketing Authorisation Holder Product name Strength Pharmaceutical Form Route of Administration MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, Parlodel 5 mg - Kapseln 5 mg Capsule Oral Use Parlodel 2,5 mg - Kapseln 2,5 mg Capsule Oral Use Parlodel SRO 10 mg - Kapseln 10 mg Capsule Oral Use MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, Parlodel SRO 2,5 mg - Kapseln 2,5 mg Capsule Oral Use Belgium Belgium MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, MEDA PHARMA GmbH Liesinger-Flur- Gasse 2c, 1230 Wien, Meda Pharma S.A. - N.V. Chaussee de la Hulpe B-1170 Brussels Meda Pharma S.A. - N.V. Chaussee de la Hulpe B-1170 Brussels Parlodel SRO 5 mg - Kapseln 5 mg Capsule Oral Use Umprel 10 mg Capsule Oral Use Umprel 5 mg Capsule Oral Use Umprel 2,5 mg Capsule Oral Use Parlodel 2.5 mg Tablet Oral Use Parlodel 10 MG 10 mg Capsule, hard Oral Use 2

3 Belgium Bulgaria Bulgaria Bulgaria Cyprus Cyprus Cyprus Cyprus Czech Republic Czech Republic Denmark Denmark Denmark Meda Pharma S.A. - N.V. Chaussee de la Hulpe B-1170 Brussels MEDOCHEMIE Limited, 1-10 Constantinoupoleos Str., Zakaki, Limassol, Cyprus NOVARTIS Pharma Sofia 1164 Square "Dzhon Paul II" office centre "Bulgaria 2000", Bulgaria SOPHARMA - Sofia 1797 bul." Kliment Ohridski" 3, Bulgaria REMEDICA LTD, P.O.Box 51706, 3508 Lemesos, Cyprus CODAL SYNTO LTD, P.O.BOX 51785, 3508 Lemesos, Cyprus DEMETRIADES & PAPAELLINAS Ltd, P.O.Box 23490, 1683, Lefkosia, Cyprus MEDOCHEMIE Limited, 1-10 Constantinoupoleos Str., Zakaki, Limassol, Cyprus MEDA PHARMA s.r.o., Záhřebská, 577, , Praha 2, Czech Republic MEDOCHEMIE Limited, 1-10 Constantinoupoleos Str., Zakaki, Limassol, Cyprus MEDA AS, Solvang 8, DK-3450 Allerød, Denmark MEDA AS, Solvang 8, DK-3450 Allerød, Denmark MEDA AS, Solvang 8, DK-3450 Allerød, Denmark Parlodel 5 mg 5 mg Capsule, hard Oral Use Medocriptine 2.5 mg Tablet Oral Use Parlodel 2.5 mg Tablet Oral Use Bromocriptine Sopharma 2.5 mg Tablet Oral Use Brameston 2.5 mg Tablet Oral Use Pirodal 2.5 mg Tablet Oral Use Parlodel 2.5 mg Tablet Oral Use Medocriptine 2.5 mg Tablet Oral Use Parlodel 2.87 mg Tablet Oral use Medocriptine 2.87 mg Tablet Oral use Parlodel 2,5 mg Tablet Oral Use Parlodel 5 mg Capsule, hard Oral Use Parlodel 10 mg Capsule, hard Oral Use 3

4 Estonia Estonia Finland Finland Finland Finland Finland GEDEON RICHTER, Gyömröi út 19-21, Budapest, HU-1103, Hungary NOVARTIS Finland Oy, Metsanneidonkuja 10 Fin ESPOO, Finland MEDA OY Lemminkäisenkatu Turku Finland MEDA OY Lemminkäisenkatu Turku Finland MEDA OY Lemminkäisenkatu Turku Finland MEDA OY Lemminkäisenkatu Turku Finland MEDA OY Lemminkäisenkatu Turku Finland MEDA PHARMA 25 boulevard de l'amiral Bruix Paris, MEDA PHARMA 25 boulevard de l'amiral Bruix Paris, MEDA PHARMA 25 boulevard de l'amiral Bruix Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, Promocriptin-Richter 2,5 mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use Parlodel 10 mg Capsule, hard Oral Use Parlodel 5 mg Capsule, hard Oral Use Parlodel 10 mg Capsule, hard Oral Use Parlodel 5 mg Capsule, hard Oral Use Parlodel 5 mg Capsule Oral Use Parlodel 10 mg Capsule Oral Use Parlodel 2,5 mg scored tablet Oral Use Bromocriptine Winthrop 2,5 mg scored tablet Oral Use Bromokin 2,5 mg scored tablet Oral Use Parlodel 2,5 mg scored tablet Oral Use 4

5 SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, SANOFI-AVENTIS 1/13 boulevard Romain Rolland Paris, MEDA PHARMA GmbH & Co. KG, Benzstr. 1, D Bad Homburg, MEDA PHARMA GmbH & Co. KG, Benzstr. 1, D Bad Homburg, MEDA PHARMA GmbH & Co. KG, Benzstr. 1, D Bad Homburg, AbZ-PHARMA Graf-Arco-Str. 3 D Ulm, BETAPHARM Arzneimittel GmbH; Kobelweg 95; D Augsburg, BETAPHARM Arzneimittel GmbH; Kobelweg 95; D Augsburg, Bromocriptine Winthrop Bromocriptine Winthrop 5 mg Capsule Oral Use 10 mg Capsule Oral Use Bromokin 5 mg Capsule Oral Use Bromokin 10 mg Capsule Oral Use Bromo-kin 2,5 mg Tablet Oral Use Pravidel 10 mg Kapseln mg Capsule, hard Oral Use Pravidel 5 mg Kapseln mg Capsule, hard Oral Use Pravidel 2,5 mg Tabletten 2.87 mg Tablet Oral Use Bromocriptin AbZ 2,5mg Tabletten 2.87 mg Tablet Oral Use Bromocriptin beta mg Capsule, hard Oral Use Bromocriptin beta 2, mg Tablet Oral Use 5

6 CT-ARZNEIMITTEL GmbH Lengeder Str. 42a D Berlin, CT-ARZNEIMITTEL GmbH Lengeder Str. 42a D Berlin, CT-ARZNEIMITTEL GmbH Lengeder Str. 42a D Berlin, bromocriptin-ct 5mg Hartkapseln bromocriptin-ct 2,5 mg Tabletten bromocriptin-ct 10mg Hartkapseln mg Capsule, hard Oral Use 2.87 mg Tablet Oral Use mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromocriptin Hexal 10 mg Kapseln mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Kamilium 10 Kps mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromocriptin Hexal 5 mg Kapseln mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromoxal 5 mg mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromocriptin Hexal 5 mg Kapseln mg Capsule, hard Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromolakt 5 mg mg Capsule Oral Use Bromoktin 5 mg mg Capsule Oral Use HEXAL AG, Industriestrasse 25,Holzkirchen, D-83607, Bromocriptin Hexal 2,5 mg Tabletten 2.87 mg Tablet Oral Use 6

7 HORMOSAN PHARMA GmbH Postfach D Frankfurt, HORMOSAN PHARMA GmbH Postfach D Frankfurt, TAURUS PHARMA GmbH Benzstr. 11 D Bad Homburg, Kirim 5 T 5.74 mg Tablet Oral Use Kirim 2, mg Tablet Oral Use Kirim gyn 2.87 mg Tablet Oral Use RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, Bromocriptin-ratiopharm 10mg Hartkapseln mg Capsule, hard Oral Use RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, Bromocriptin-ratiopharm 5mg Hartkapseln mg Capsule, hard Oral Use RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, Bromocriptin-ratiopharm 2,5mg Tabletten 2.87 mg Tablet Oral Use Greece Greece SANDOZ Pharmaceuticals GmbH, Raiffeisenstr. 1, D Holzkirchen, SANDOZ Pharmaceuticals GmbH, Raiffeisenstr. 1, D Holzkirchen, MEDA PHARMACEUTICALS S.A. Greece, 3 Evritanias Street, Halandri Attikis 15231, Greece MEDA PHARMACEUTICALS S.A. Greece, 3 Evritanias Street, Halandri Attikis 15231, Greece Bromocriptin Sandoz 10mg Hartkapseln Bromocriptin Sandoz 5mg Hartkapseln mg Capsule, hard Oral Use mg Capsule, hard Oral Use Parlodel 5 mg Capsule, hard Oral Use Parlodel 10 mg Capsule, hard Oral Use 7

8 Hungary Iceland Iceland Iceland Ireland Ireland Italy Italy Italy Italy Latvia Latvia Latvia GEDEON RICHTER, Gyömröi út 19-21, Budapest, HU-1103, Hungary ICEPHARMA hf., Lynghálsi 13, 110 Reykjavík, Iceland ICEPHARMA hf., Lynghálsi 13, 110 Reykjavík, Iceland ICEPHARMA hf., Lynghálsi 13, 110 Reykjavík, Iceland MEDA Health Sales Ireland Ltd, Office 10 Dunboyne Business Park, Dunboyne, Co. Meath, Ireland MEDA Health Sales Ireland Ltd, Office 10 Dunboyne Business Park, Dunboyne, Co. Meath, Ireland MEDA PHARMA SpA - Via Le Brenta, , Milano, Italy MEDA PHARMA SpA - Via Le Brenta, , Milano, Italy DOROM Srl - VIA Giulio Richard 7 - MILANO (IT), Italy DOROM Srl - VIA Giulio Richard 7 - MILANO (IT), Italy LEK PHARMACEUTICALS Pr.d.d., Verovškova 57, SI-1000, Ljubljana, Slovenia GEDEON RICHTER, Gyömröi út 19-21, Budapest, HU-1103, Hungary NOVARTIS Finland Oy, Metsanneidonkuja 10 Fin ESPOO, Finland Bromocriptine-Richter 2.5 mg Tablet Oral Use Parlodel 5 mg Capsule, hard Oral Use Parlodel 10 mg Capsule, hard Oral Use Parlodel 2,5 mg Tablet Oral Use Parlodel 2.5 mg Tablet Oral Use Parlodel 5 mg Capsule Oral Use Parlodel 10 mg Capsule Oral Use Parlodel 5 mg Capsule Oral Use Bromocriptina Dorom 10 mg Capsule Oral Use Bromocriptina Dorom 5 mg Capsule Oral Use Bromergon 2,5 mg Tablet Oral Use Bromocriptin-Richter 2,5 mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use 8

9 Lithuania Lithuania Lithuania Netherlands Netherlands Netherlands Poland Poland GEDEON RICHTER, Gyömröi út 19-21, Budapest, HU-1103, Hungary NOVARTIS Finland Oy, Metsanneidonkuja 10 Fin ESPOO, Finland POLI INDUSTRIA chimica S.p.A. Via Volturno 45/48-Quinto de Stampi Rozzano Milano, Italy MEDA PHARMA GmbH, Benestrasse 1, D BAD Hambourg, MEDA PHARMA GmbH, Benestrasse 1, D BAD Hambourg, MEDA PHARMA GmbH, Benestrasse 1, D BAD Hambourg, MEDA PHARMA B.V. Krijgsman 20, 1186 DM AMSTELVEEN/NL, Netherlands MEDA PHARMA B.V. Krijgsman 20, 1186 DM AMSTELVEEN/NL, Netherlands MEDA PHARMA B.V. Krijgsman 20, 1186 DM AMSTELVEEN/NL, Netherlands LEK S.A., ul. Podlipie 16, Stryków, Poland FILOFARM, Farmaceutyczna Spółdzielnia Pracy "Filofarm", ul. Pułaskiego 39, Bydgoszcz, Poland Bromocriptin-Richter 2,5 mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use Bromocriptine Poli 2,5 mg Tablet Oral Use Pravidel 2.5 mg Tablet Oral Use Pravidel 5 mg Capsule Oral Use Pravidel 10 mg Capsule Oral Use Parlodel 10 mg 10 mg Capsule Oral Use Parlodel 2.5 mg 2.5 mg Tablet Oral Use Parlodel 5 mg 5 mg Tablet Oral Use Bromergon 2,5 mg Tablet Oral Use Bromocorn 2,87 mg Tablet Oral Use 9

10 Poland Poland Portugal Portugal Portugal Meda Aktiebolag - Pipers vag 2, Box SE Solana - Sweden POLFA, Grodziskie Zakłady Farmaceutyczne POLFA Sp. z o.o., ul. Poniatowskiego 5, Grodzisk Mazowiecki, Poland MEDA PHARMA - Produtos Farmacêuticos, S.A.Rua do Centro Cultural, Lisboa, Portugal MEDA PHARMA - Produtos Farmacêuticos, S.A.Rua do Centro Cultural, Lisboa, Portugal MEDA PHARMA - Produtos Farmacêuticos, S.A.Rua do Centro Cultural, Lisboa, Portugal Parlodel 2,5 mg Tablet Oral Use Ergolaktyna 2,5 mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use Parlodel 5 mg Capsule Oral Use Parlodel 10 mg Capsule Oral Use Portugal GENERIS Farmacêutica, S.A. Office Park da Beloura - Edifício 4 - Quinta da Beloura Sintra Portugal Bromocriptina Generis 2,5 mg Comprimidos 2,5 mg Tablet Oral Use Romania Slovak Republic Slovak Republic S.C. BIOFARM S.A., Str. Logofat Tautu nr. 99, sector 3, Bucharest, Romania MEDA PHARMA s.r.o., Záhřebská, 577, , Praha 2, Czech Republic MEDOCHEMIE Limited, 1-10 Constantinoupoleos Str., Zakaki, Limassol, Cyprus Brocriptin 2.5mg Tablet Oral Use Parlodel 2,5 mg Tablet Oral Use Medocriptine 2,5 mg 2,5 mg Tablet Oral Use 10

11 Slovenia Spain Spain Sweden Sweden Sweden United Kingdom United Kingdom United Kingdom LEK farmacevtska družba, d.d., Verovškova 57, 1000 Ljubljana, Slovenia MEDA PHARMA SAU AVDA Castilla, 2 Edif Berlin 2º planta, parque empresarial San Fernando de Henares, Spain MEDA PHARMA SAU AVDA Castilla, 2 Edif Berlin 2º planta, parque empresarial San Fernando de Henares, Spain MEDA AB, Box 906, , Solna Sweden MEDA AB, Box 906, , Solna Sweden MEDA AB, Box 906, , Solna Sweden MEDA PHARMACEUTICALS LIMITED; Building 2000, Beach Drive, Cambridge Research Park, Waterbeach, Cambridgeshire, CB5 9PD, UK MEDA PHARMACEUTICALS LIMITED; Building 2000, Beach Drive, Cambridge Research Park, Waterbeach, Cambridgeshire, CB5 9PD, UK MEDA PHARMACEUTICALS LIMITED; Building 2000, Beach Drive, Cambridge Research Park, Waterbeach, Cambridgeshire, CB5 9PD, UK Bromergon 2,5 mg Tablet Oral Use Parlodel 2,5 mg Comprimidos 2,5 mg Tablet Oral Use Parlodel 5 mg Capsulas 5 mg Capsule Oral Use Pravidel 2,5 mg Tablet Oral Use Pravidel 5 mg Capsule, hard Oral Use Pravidel 10 mg Capsule, hard Oral Use Parlodel 2.5 mg Tablets 5 mg Tablet Oral Use Parlodel 2.5 mg Tablets 10 mg Tablet Oral Use Parlodel 2.5 mg Tablets 2.5 mg Tablet Oral Use 11

12 United Kingdom MEDA PHARMACEUTICALS LIMITED; Building 2000, Beach Drive, Cambridge Research Park, Waterbeach, Cambridgeshire, CB5 9PD, UK Parlodel 1 mg Tablets 1 mg Tablet Oral Use United Kingdom NORTON HEALTHCARE Limited, Albert Basin, Royal Docks, London E16 2QJ, UK Bromocriptine Tablets BP 2.5 mg 2.5 mg Tablet Oral Use United Kingdom GENERICS (UK) Limited, Station Close, Potters Bar, Herts EN6 1TL, UK Bromocriptine Tablets BP 2.5 mg 2.5 mg Tablet Oral Use United Kingdom United Kingdom NOVARTIS PHARMACEUTICALS UK LIMITED, Frimley Business Park, Frimley, Camberley, Surrey, United Kingdom, GU16 7SR, NOVARTIS PHARMACEUTICALS UK LIMITED, Frimley Business Park, Frimley, Camberley, Surrey, United Kingdom, GU16 7SR, Parlodel LAR Injection 50 mg 50 mg Powder for Injection Intramuscular Use Parlodel LAR Injection 100 mg 100 mg Powder for Injection Intramuscular Use 12

13 Dihydroergocryptine containing medicinal products with Marketing Authorisation in the European Union Member State Marketing Authorisation Holder Product name Strength Pharmaceutical Form Route of Administration Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal RATIOPHARM Arzneimittel Vertriebs- GmbH, Albert-Schweitzer Gasse Wien, RATIOPHARM Arzneimittel Vertriebs- GmbH, Albert-Schweitzer Gasse Wien, SANOVA Pharma GmbH, Haidestraße 4, 1110 Wien, Hydergin - Fas 4,5 mg - Filmtabletten 4,5 mg Tablet Oral Use Hydergin 1 mg/ml - Tropfen 1 mg/ml Oral Drops Oral Use Hydergin 3 mg/ml - Tropfen 3 mg/ml Oral Drops Oral Use Hydergin 1 mg - Tabletten 1 mg Tablet Oral Use Hydergin 2 mg - Tabletten 2 mg Tablet Oral Use Hydergin 0,3 mg/1 ml Ampullen 0,3 mg/1 m Solution for Injection Intravenous use Hydergin SRO 6 mg - Kapseln 6 mg Capsule Oral Use Co-Dergocrin "ratiopharm" retard 5 mg - Kapseln Co-Dergocrin "ratiopharm" retard 2,5 mg - Kapseln 5 mg Capsule Oral Use 2,5 mg Capsule Oral Use Dorehydrin 1 mg/ml - Tropfen 1 mg/ml Oral Drops Oral Use 13

14 Belgium Belgium Belgium Belgium Belgium Belgium Belgium SANOVA Pharma GmbH, Haidestraße 4, 1110 Wien, SANOVA Pharma GmbH, Haidestraße 4, 1110 Wien, WABOSAN Arzneimittelvertriebs GmbH Anton Anderer Platz 6/1, 1210 Wien, WABOSAN Arzneimittelvertriebs GmbH Anton Anderer Platz 6/1, 1210 Wien, WABOSAN Arzneimittelvertriebs GmbH Anton Anderer Platz 6/1, 1210 Wien, NOVARTIS PHARMA nv. Medialaan Vilvoorde, Belgium NOVARTIS PHARMA nv. Medialaan Vilvoorde, Belgium NOVARTIS PHARMA nv. Medialaan Vilvoorde, Belgium NOVARTIS PHARMA nv. Medialaan Vilvoorde, Belgium LABORATOIRES PHARMACOBEL Avenue de Seheut, Bruxelles, Belgium NYCOMED BELGIUM Gentsesteenweg Brussel, Belgium NYCOMED BELGIUM Gentsesteenweg Brussel, Belgium Dorehydrin retard 2,5 mg - Kapseln Dorehydrin retard 4,5 mg - Kapseln 2,5 mg Capsule Oral Use 4,5 mg Capsule Oral Use Ergomed retard- Kapseln 0,875 mg Capsule Oral Use Ergomed - Tabletten 0,33 mg Tablet Oral Use Ergomed - Tropfen 0,33 mg/ml Oral Drops Oral Use Hydergine 1 mg / ml Oral Drops, Solution Oral Use Hydergine 1,5 mg 1.5 mg Tablet Oral Use Hydergine 4.5 mg 4.5 mg Tablet Oral Use Hydergine FAS 4.5 mg 4.5 mg Gastro-Resistant Tablet Oral Use Dystonal 2,5 mg (N.F.) 2.5 mg Tablet Oral Use Stofilan 1.5 mg Tablet Oral Use Stofilan 1 mg / ml Oral Solution Oral Use 14

15 Belgium Belgium Belgium Belgium Belgium Bulgaria Bulgaria NYCOMED BELGIUM Gentsesteenweg Brussel, Belgium SANDIPRO s.a. chaussée de Gand, Bruxelles, Belgium SANDIPRO s.a. chaussée de Gand, Bruxelles, Belgium SANDIPRO s.a. chaussée de Gand, Bruxelles, Belgium SANDIPRO s.a. chaussée de Gand, Bruxelles, Belgium POLI INDUSTRIA chimica S.p.A., Via Volturno 45/48-Quinto de Stampi Rozzano Milano, Italy POLI INDUSTRIA chimica S.p.A., Via Volturno 45/48-Quinto de Stampi Rozzano Milano, Italy Stofilan 4.5 mg Tablet Oral Use IBEXONE 1.5 mg 1.5 mg Tablet Oral Use IBEXONE 1 mg / ml Oral Solution Oral Use IBEXONE 4.5 mg 4.5 mg Tablet Oral Use IBEXONE 3 mg / ml Oral Solution Oral Use Almirid 5 5 mg Capsule, hard Oral Use Almirid 5 20 mg Tablet Oral Use Czech Republic Czech Republic Finland Finland POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, Novartis Finland Oy Metsänneidonkuja 10, ESPOO Novartis Finland Oy Metsänneidonkuja 10, ESPOO Almirid 20 mg Tablet Oral Use Almirid 5 mg Capsule, hard Oral Use Hydergin 1mg Tablet Oral Use Hydergin 1.5mg Tablet Oral Use 15

16 Novartis Pharma SAS, 2 & 4 Rue Lionel Terray Rueil Malmaison Cedex, Novartis Pharma SAS, 2 & 4 Rue Lionel Terray Rueil Malmaison Cedex, Novartis Pharma SAS, 2 & 4 Rue Lionel Terray Rueil Malmaison Cedex, DESITIN ARZNEIMITTEL GmbH Postfach D Hamburg, DESITIN ARZNEIMITTEL GmbH Postfach D Hamburg, DESITIN ARZNEIMITTEL GmbH Postfach D Hamburg, TAURUS PHARMA GmbH Benzstr. 11 D Bad Homburg, TAURUS PHARMA GmbH Benzstr. 11 D Bad Homburg, TAURUS PHARMA GmbH Benzstr. 11 D Bad Homburg, Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Hydergine 0.3 mg/1ml Solution for Injection Oral Use Hydergine 1 mg/1ml Oral Solution Oral Use Hydergine 4.5 mg Tablet Oral Use Almirid 20 mg Tablet Oral Use Almirid 40 mg Tablet Oral Use Almirid 5 mg Capsule Oral Use Cripar mg Tablet Oral Use Cripar forte mg Tablet Oral Use Cripar 5 5 mg Capsule Oral Use Hydergin 1mg/ml Tropfloesung mg Oral Drops, Solution Oral Use Hydergin forte 2mg Tabletten mg Tablet Oral Use 16

17 Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal Defiante Farmaceutica Lda., Rua dos Ferreiros 260, PT Funchal/Madeira, Portugal DESITIN ARZNEIMITTEL GmbH Postfach D Hamburg, DESITIN ARZNEIMITTEL GmbH Postfach D Hamburg, OPFERMANN ARZNEIMITTEL GmbH Opfermann Arzneimittel GmbH Robert-Koch-Str. 2 D Wiehl, OPFERMANN ARZNEIMITTEL GmbH Opfermann Arzneimittel GmbH Robert-Koch-Str. 2 D Wiehl, OPFERMANN ARZNEIMITTEL GmbH Opfermann Arzneimittel GmbH Robert-Koch-Str. 2 D Wiehl, Hydergin forte 2mg/ml Tropfloesung 0.67 mg Oral Drops, Solution Oral Use Hydergin Spezial 1.33 mg Film-coated Tablet Oral Use Ergodesit forte 2 mg 0.66 mg Tablet Oral Use Ergodesit spezial 5 mg 1.66 mg Prolonged-Release Tablet Oral Use Orphol forte 3 mg/ml 1. mg Oral Solution Oral Use Orphol Spezial 1.5 mg Tablet Oral Use Orphol Brausetabletten 1.5 mg Effervescent Tablet Oral Use Amdipharm Limited Temple Chambers 3 Burlington Road IRL-Dublin 4, Ireland DCCK Tropfloesung 1 mg Prolonged-Release Capsule, hard Oral Use 17

18 Amdipharm Limited Temple Chambers 3 Burlington Road IRL-Dublin 4, Ireland DCCK Depot 4,5 1.5 mg Prolonged-Release Capsule, hard Oral Use Greece Greece Greece Hungary Hungary Ireland Ireland FARMASAN Arzneimittel GmbH & Co.KG, Postfach D Karlsruhe, FARMASAN Arzneimittel GmbH & Co.KG, Postfach D Karlsruhe, RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, RATIOPHARM Graf-Arco-Strasse 3, DE Ulm, PHARMANEL PHARMACEUTICALS S.A., Marathonos 106, Gerakas 15344, Greece PHARMANEL PHARMACEUTICALS S.A., Marathonos 106, Gerakas 15344, Greece Novartis (Hellas) S.A.C.I., 12 Klm National Road No 1, GR-14451, Athens, Greece POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, Sponsin forte Sponsin spezial Hydro-Cebral-ratiopharm Tropfen Hydro-Cebral-ratiopharm 2,5 mg Hydro-Cebral-ratiopharm 5,0 mg mg 1.5 mg Prolonged-Release Capsule, hard Prolonged-Release Capsule, hard Oral Use Oral Use 0.33 mg Oral Solution Oral Use mg mg Prolonged-Release Capsule, hard Prolonged-Release Capsule, hard Oral Use Oral Use Daverium 5 mg Capsule, hard Oral Use Daverium 20 mg Tablet Oral Use Hydergine LPD 0.1% 15 ml Oral Solution Oral Use Almirid 20mg Tablet Oral Use Almirid 5mg Capsule Oral Use Almirid 5mg Capsule Oral Use Almirid 20 mg Tablet Oral Use 18

19 Italy Italy Italy MARVECSPHARMA SERVICES Srl - Via Felice Casati, Milano, Italy Novartis Farma S.P.A. Largo Umberto Boccioni Origgio Varese, Italy Novartis Farma S.P.A. Largo Umberto Boccioni Origgio Varese, Italy NOVARTIS Pharma GmbH Roonstrasse 25, D Nurnberg, Daverium 20 mg Tablet Oral Use Hydergina 1 mg Oral Solution Oral Use Hydergina 1.5 mg Tablet Oral Use Hydergin 1mg/ml Tropfloesung mg Oral Drops, Solution Oral Use NOVARTIS Pharma GmbH Roonstrasse 25, D Nurnberg, Hydergin forte 2mg/ml Tropfloesung 0.67 mg Oral Drops, Solution Oral Use Netherlands Poland Portugal Portugal Portugal Portugal NOVARTIS Pharma GmbH Roonstrasse 25, D Nurnberg, CENTRAFARM SERVICES B.V.; Nieuwe Donk 9; 4879 AC ETTEN- LEUR/NL, Netherlands POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, Novartis Farma - Produtos Farmacêuticos, S.A. - Rua do Centro Empresarial, Edifício 8, Quinta da Beloura, Sintra, Portugal Novartis Farma - Produtos Farmacêuticos, S.A. - Rua do Centro Empresarial, Edifício 8, Quinta da Beloura, Sintra, Portugal Hydergin Spezial 1.33 mg Film-coated Tablet Oral Use Co-dergocrinemesilaat 1.5 mg Tablet Oral Use Almirid 20 mg Tablet Oral Use Cripar mg Tablet Oral Use Cripar 5 5 mg Capsule Oral Use Hydergine 1.5 mg 1.5 mg Tablet Oral Use Hydergine 4.5 mg 4.5 mg Tablet Oral Use 19

20 Portugal Portugal Slovak Republic Slovak Republic Spain Spain Sweden United Kingdom United Kingdom Novartis Farma - Produtos Farmacêuticos, S.A. - Rua do Centro Empresarial, Edifício 8, Quinta da Beloura, Sintra, Portugal Novartis Farma - Produtos Farmacêuticos, S.A. - Rua do Centro Empresarial, Edifício 8, Quinta da Beloura, Sintra, Portugal POLICHEM S.A. 50, Val Fleuri, L-1526, POLICHEM S.A. 50, Val Fleuri, L-1526, Novartis Farmacéutica, S.A., Gran Via de los Corts Catalanes, número 184, Barcelona, Spain Novartis Farmacéutica, S.A., Gran Via de los Corts Catalanes, número 184, Barcelona, Spain Novartis Sverige AB, Kemistvägen 1B, Box 1150, Täby, Sweden Novartis Pharmaceuticals Ltd., Frimley Business Park, Frimley, Camberley, Surrey GU16 7SR, UK Novartis Pharmaceuticals Ltd., Frimley Business Park, Frimley, Camberley, Surrey GU16 7SR, UK Hydergine 1mg/ml 1 mg/ml Oral Drops, Solution Oral Use Hydergine 3mg/ml 3 mg/ml Oral Drops, Solution Oral Use Almirid 20 mg Tablet Oral Use Almirid 5 mg Capsule Oral Use Hydergina 4.5 mg Tablet Oral Use Hydergina 1 mg/ml Oral Solution Oral Use Hydergine 1 mg Tablet Oral Use Hydergine 1.5 mg 1.5 mg Tablet Oral Use Hydergine 4.5 mg 4.5 mg Tablet Oral Use 20

21 Lisuride containing medicinal products with Marketing Authorisation in the European Union Member State Marketing Authorisation Holder Product name Strength Pharmaceutical Form Route of Administration Italy Italy BAYER GmbH, Herbststraße, 6-10, 1160 Wien, LABO LISA pharm 9 bis boulevard J. Jaures Boulogne Billancourt, Bayer Schering Pharma, ZI roubaix est rue de touflers, Lys-les-Lannoy, Bayer Schering Pharma, ZI roubaix est rue de touflers, Lys-les-Lannoy, BAYER Vital GmbH, D Leverkusen, BAYER Vital GmbH, D Leverkusen, SCHERING SpA - Via E.Schering, Segrate (MI), Italy SCHERING SpA - Via E.Schering, Segrate (MI), Italy Dopergin - Tabletten 0,2 mg Tablet Oral Use Arolac 0,2mg Tablet Oral Use Dopergine 0,2 mg Tablet Oral Use Dopergine 0,5mg Tablet Oral Use Dopergin-0,5 mg Tablette 0.5 mg Tablet Oral Use Dopergin-0,2 mg Tablette 0.2 mg Tablet Oral Use Dopergin 0,2 mg Tablet Oral Use Dopergin 0,5 mg Tablet Oral Use Spain Quimica Farmaceutica Bayer, SL, Pau Claris, 196, Barcelona, Spain Dopergin 0,2 mg comprimidos 0,2 mg Tablet Oral Use 21

22 ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLETS PRESENTED BY THE EMEA 22

23 SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF BROMOCRIPTINE, DIHYDROERGOCRYPTINE AND LISURIDE AND ASSOCIATED NAMES (SEE ANNEX I) Bromocriptine, dihydroergocryptine and lisuride belong to the class of ergot derived dopamine agonists, which also comprises cabergoline and pergolide. All active substances are authorised at the level of the Member States. Ergot derived dopamine agonists are mainly used to treat Parkinson s disease, either on their own or in combination with other medicines. They are also used to treat conditions including hyperprolactinaemia and prolactinoma, and to prevent lactation and migraine. Ergot-derived dopamine agonists have been associated with an increased risk of fibrotic disorders and valvular heart disease. This has been subject to previous reviews leading to risk minimisation measures at national level. As a result, cabergoline and pergolide containing medicinal products are indicated only as 2nd line therapy in Parkinson s disease, and their use is contraindicated for patients with evidence of valve problems. On 21 June 2007, the UK asked the CHMP, under article 31 of Directive 2001/83/EC, as amended, to review the risk of fibrosis and cardiac valvulopathy associated with the use of all ergot-derived dopamine agonists, and to provide an opinion on whether the marketing authorisations for all products of the class should be maintained, varied, suspended or withdrawn. The CHMP reviewed all of the information made available by marketing authorisation holders (MAH) on the risk of fibrosis and cardiac valvulopathy from clinical trials, observational studies and spontaneous reports. Spontaneous cases of fibrotic reactions were reported for all ergot derived dopamine agonists, especially at high doses and after long period of treatment. However, cases of valvulopathy were reported for bromocriptine, cabergoline, dihydroergocryptine and pergolide, but not for lisuride. Overall, data from spontaneous reports indicate that subjects using carbergoline and pergolide are more at risk for fibrotic events and valvulopathy than subjects using bromocriptine, lisuride or dihydroergocryptine. The majority of reported fibrotic events were not completely reversible although symptomatic improvement occurs for various reasons and indeed occasionally fibrosis may regress. For bromocriptine, dihydroergotamine and lisuride, no fibrotic events have been reported by MAHs from clinical trials or observational studies. Four main observational studies looked into the risk of cardiac valvulopathy in patients treated with dopamine agonists for Parkinson s disease (Zanettini et al., NEJM, 2007; Schade et al., NEJM 2007; Yamamoto et al., Neurology 2006; Peralta et al., Movement Disorders 2006). The Schade study reported higher adjusted incidence rate ratio (IRR) for symptomatic valvular regurgitation for cabergoline and pergolide, compared to bromocriptine, lisuride, and non ergot derived dopamine agonists pramipexole and ropirinole for which no cases were reported. The mechanism of fibrotic reaction induced by ergot alkaloids has not been completely clarified yet. The stimulation of the 5-HT2B receptor agonists is considered the most plausible mechanism that induces cardiac valvulopathy, although other mechanisms may be involved. The degree of 5-HT2B receptor agonism varies across ergot derived dopamine agonists and fits well with the difference in incidence rates of fibrotic events for the different ergot-products (C.Hofmann et al., Clin Neuropharmacol, 2006). Whether this mechanism also applies to the non-cardiac fibrotic events is unclear. 23

24 At its June 2008 meeting, the CHMP concluded that the amount of evidence on the risk of fibrotic events, including valvulopathy, is not equal for all ergot-derived dopamine agonists. For carbergoline and pergolide an increased risk of fibrotic events is considered well established. For bromocriptine, dihydroergocryptine and lisuride an increased risk cannot be excluded based on the amount of evidence available. In view of the above, the CHMP recommended the maintenance of the marketing authorisation for bromocriptine, dihydroergocryptine and lisuride containing medicinal products with amendments to their product information (Summary of product characteristics and Package leaflet), as outlined below. For bromocriptine and dihydroergocryptine: A contraindication for patients treated for a long period and with pre-existing cardiac valulopathy. For bromocriptine: Restriction of the maximum dose to 30 mg per day. For bromocriptine, dihydroergocryptine and lisuride: A warning on the possible risk of fibrosis in patients taking these medicines at high doses for long periods. This warning includes recommendations for the monitoring of patients for signs of fibrosis during treatment. In view of the differences in the level risk amongst ergot derived dopamine agonists, the CHMP recommended that a separate opinion is issued for cabergoline and pergolide. GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLETS Whereas, - The CHMP considered the referral made under Article 31 of Directive 2001/83/EC, as amended, for medicinal products containing bromocriptine, cabergoline, dihydroergocryptine, lisuride and pergolide. - In view of the available data, the Committee concluded that the risk of fibrotic events, including valvulopathy, is not equal for all ergot-derived dopamine agonists. For bromocriptine, dihydroergocryptine and lisuride, an increased risk of fibrosis, including cardiac valvulopathy, cannot be excluded. - The CHMP, as a consequence, recommended amendments to the relevant sections of the Summary of product characteristics and Package leaflets for the medicinal products containing bromocriptine, dihydroergocryptine and lisuride (see Annex III). 24

25 ANNEX III AMENDMENTS TO THE SUMMARIES OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLETS 25

26 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE SUMMARY OF PRODUCT CHARACTERISTICS FOR BROMOCRIPTINE CONTAINING MEDICINAL PRODUCTS 4.2 Posology and method of administration The following should be reflected as appropriate: Restriction of maximum dose to 30 mg/day. 4.3 Contra-indications: [ ] For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography. 4.4 Special warnings and precautions for use: [ ] Among patients on bromocriptine, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine therapy should be contemplated. In a few patients on bromocriptine, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at early reversible stage it is recommended that its manifestations (e.g. back pain, oedema of the lower limbs, impaired kidney function) should be watched in this category of patients. Bromocriptine medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected. 4.8 Undesirable effects: The following should be included under cardiac disorders: Very rare: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion). 26

27 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE PACKAGE LEAFLET FOR BROMOCRIPTINE CONTAINING MEDICINAL PRODUCTS Section 2 Before you take [product name] : Do not take [product name] if you: [ ] - will be treated with [product name] for a long period and have or had fibrotic reactions (scar tissue) affecting your heart. Take special care with [product name] [ ] - If you have or had fibrotic reactions (scar tissue) affecting your heart, lungs or abdomen. In case you are treated with [product name] for a long period, your physician will check before starting treatment whether your heart, lungs and kidneys are in good condition. He/she will also have an echocardiogram (an ultrasound test of the heart) taken before treatment is started. During treatment your physician will pay special attention to any signs which may be related to fibrotic reactions. If necessary he/she will have an echocardiogram taken. If fibrotic reactions occur treatment will have to be discontinued. Section 4 Possible side effects : [ ] Very rare side effect (affecting less than one person in10.000): heart valve and related disorders e.g. inflammation (pericarditis) or leaking of fluid in the pericardium (pericardial effusion). The early symptoms may be one or more of the following: difficulty breathing, shortness of breath, chest or back pain and swollen legs. If you experience any one of these symptoms you must tell your doctor immediately. 27

28 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE SUMMARY OF PRODUCT CHARACTERISTICS FOR DIHYDROERGOCRYPTINE CONTAINING MEDICINAL PRODUCTS 4.3 Contraindications: [ ] For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography. 4.4 Special warnings and precautions for use: [ ] Among patients on dihydroergocryptine, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of dihydroergocryptine therapy should be contemplated. Particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported in rare cases. To ensure recognition of retroperitoneal fibrosis at early reversible stage it is recommended that its manifestations (e.g. back pain, oedema of the lower limbs, impaired kidney function) should be watched in this category of patients. Dihydroergocryptine medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected. 4.8 Undesirable effects: The following should be included under Cardiac disorders: Very rare: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion). 28

29 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE PACKAGE LEAFLET FOR DIHYDROERGOCRYPTINE CONTAINING MEDICINAL PRODUCTS Section 2 Before you take [product name] : Do not take [product name] if you: [ ] -will be treated with [product name] for a long period andhave or had fibrotic reactions (scar tissue) affecting your heart. Take special care with [product name] [ ] - If you have or had fibrotic reactions (scar tissue) affecting your heart, lungs or abdomen. In case you are treated with [product name] for a long period, your physician will check before starting treatment whether your heart, lungs and kidneys are in good condition. He/she will also have an echocardiogram (an ultrasound test of the heart) taken before treatment is started. During treatment your physician will pay special attention to any signs which may be related to fibrotic reactions. If necessary he/she will have an echocardiogram taken. If fibrotic reactions occur treatment will have to be discontinued. Section 4 Possible side effects : [ ] Very rare side effect (affecting less than one person in ): heart valve and related disorders e.g. inflammation (pericarditis) or leaking of fluid in the pericardium (pericardial effusion). The early symptoms may be one or more of the following: difficulty breathing, shortness of breath, chest or back pain and swollen legs. If you experience any one of these symptoms you must tell your doctor immediately. 29

30 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE SUMMARY OF PRODUCT CHARACTERISTICS FOR LISURIDE CONTAINING MEDICINAL PRODUCTS 4.4 Special warnings and precautions for use [ ] Lisuride is an ergot derivative. After prolonged use of ergot derivatives, including lisuride inflammatory changes of a fibrotic type have been detected with serous disorders such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusions and retroperitoneal fibrosis. Since these changes are of insidious onset, patient should be monitored throughout the treatment, paying special attention to the appearance of signs and symptoms suggestive of an inflammatory disorder of a fibrotic or serous type. If a fibrotic disorder is suspected, the treatment should be halted and the diagnosis confirmed by performance of appropriate tests such as erythrocyte sedimentation rate, determination of serum creatinine and diagnostic imaging procedures (e.g. chest X-ray, echocardiography). 4.8 Undesirable effects: The following should be included under Cardiac disorders: [ ] Very rare: pericarditis, and pericardial effusion. In patients treated with ergot derivates cardiac valvulopathy (including regurgitation) has been reported. 30

31 AMENDMENTS TO BE INCLUDED IN THE RELEVANT SECTIONS OF THE PACKAGE LEAFLET FOR LISURIDE CONTAINING MEDICINAL PRODUCTS Section 2 Before you take [product name] : Take special care with [product name] [ ] - If you have or had fibrotic reactions (scar tissue) affecting your heart, lungs or abdomen. Before treatment your physician may check whether your heart, lungs and kidneys are in good condition. During treatment your physician will pay special attention to any signs which may be related to fibrotic reactions. If necessary he/she will have an echocardiogram taken (an ultrasound test of your heart). If fibrotic reactions occur treatment will have to be discontinued. Section 4 Possible side effects : [ ] In patients treated with ergot derivatives such as lisuride cases of pericarditis (inflammation of the outer lining of the heart) and pericardial effusion (accumulation of fluid between the outer lining of the heart and the heart itself) have been reported very rarely (affecting less than one person in ). Also, effects on the heart valve have been observed in patients treated with ergot derivatives. The early symptoms of these effects on the heart may be one or more of the following: difficulty breathing, shortness of breath, chest or back pain and swollen legs. If you experience any one of these symptoms you must tell your doctor immediately. 31